Bertin J, Guo Y, Wang L, Srinivasula S M, Jacobson M D, Poyet J L, Merriam S, Du M Q, Dyer M J, Robison K E, DiStefano P S, Alnemri E S
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
J Biol Chem. 2000 Dec 29;275(52):41082-6. doi: 10.1074/jbc.C000726200.
BCL10/CLAP is an activator of apoptosis and NF-kappaB signaling pathways and has been implicated in B cell lymphomas of mucosa-associated lymphoid tissue. Although its role in apoptosis remains to be determined, BCL10 likely activates NF-kappaB through the IKK complex in response to upstream stimuli. The N-terminal caspase recruitment domain (CARD) of BCL10 has been proposed to function as an activation domain that mediates homophilic interactions with an upstream CARD-containing NF-kappaB activator. To identify upstream signaling partners of BCL10, we performed a mammalian two-hybrid analysis and identified CARD9 as a novel CARD-containing protein that interacts selectively with the CARD activation domain of BCL10. When expressed in cells, CARD9 binds to BCL10 and activates NF-kappaB. Furthermore, endogenous CARD9 is found associated with BCL10 suggesting that both proteins form a pre-existing signaling complex within cells. CARD9 also self-associates and contains extensive coiled-coil motifs that may function as oligomerization domains. We propose here that CARD9 is an upstream activator of BCL10 and NF-kappaB signaling.
BCL10/CLAP是凋亡和核因子κB信号通路的激活剂，与黏膜相关淋巴组织的B细胞淋巴瘤有关。尽管其在凋亡中的作用尚待确定，但BCL10可能通过IKK复合物响应上游刺激激活核因子κB。BCL10的N端半胱天冬酶募集结构域（CARD）被认为是一个激活结构域，可介导与上游含CARD的核因子κB激活剂的同源相互作用。为了鉴定BCL10的上游信号伴侣，我们进行了哺乳动物双杂交分析，并鉴定出CARD9是一种新型的含CARD蛋白，它与BCL10的CARD激活结构域选择性相互作用。当在细胞中表达时，CARD9与BCL10结合并激活核因子κB。此外，发现内源性CARD9与BCL10相关联，这表明这两种蛋白在细胞内形成了一个预先存在的信号复合物。CARD9也能自我缔合，并含有广泛的卷曲螺旋基序，可能作为寡聚化结构域发挥作用。我们在此提出，CARD9是BCL10和核因子κB信号的上游激活剂。
